Aims/hypothesis: Liver X receptors (LXR) are important transcriptional regulators of lipid and glucose metabolism. Our previous report demonstrated that LXR activation inhibited pancreatic beta cell proliferation through cell cycle arrest. Here we explore the role of LXR activation in beta cell insulin secretion and the underlying mechanism that might be involved.
Methods: Mouse pancreatic islets or insulin-secreting MIN6 cells were exposed to the LXR agonist, T0901317, and insulin secretion, glucose and fatty acid oxidation, and lipogenic gene expression were assessed. The unsaturated fatty acid eicosapentaenoic acid and the dominant negative sterol regulatory element binding protein 1c (SREBP1c) were used to inhibit endogenous SREBP1c and evaluate the involvement of SREBP1c in beta cell dysfunction induced by LXR activation.
Results: Treatment with the LXR agonist decreased beta cell glucose sensitivity and impaired glucose-stimulated insulin secretion in vivo and in vitro. This was accompanied by derangements of beta cell glucose oxygen consumption, glucose oxidation, ATP production and intracellular voltage-gated calcium channel flux. LXR activation also regulated the expression of lipid metabolism-related genes such as Fas, Acc (also known as Acaca) and Cpt1a, and led to intracellular lipid accumulation. Further studies revealed that inhibition of SREBP1c abolished LXR activation-induced lipid accumulation and improved beta cell glucose metabolism, ATP production and insulin secretion.
Conclusions/interpretation: Our data reveal that aberrant activation of LXR reproduced the phenomenon of beta cell dysfunction in the development of type 2 diabetes in vitro and in vivo. Upregulation of SREBP1c production and the lipotoxicity mediated by it played a central role in this process.